Autism-associated chromatin regulator Brg1/SmarcA4 is required for synapse development and myocyte enhancer factor 2-mediated synapse remodeling

Zilai Zhang, Mou Cao, Chia Wei Chang, Cindy Wang, Xuanming Shi, Xiaoming Zhan, Shari G. Birnbaum, Ilya Bezprozvanny, Kimberly M. Huber, Jiang I. Wu

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8 Citations (Scopus)

Abstract

Synapse development requires normal neuronal activities and the precise expression of synapse-related genes. Dysregulation of synaptic genes results in neurological diseases such as autism spectrum disorders (ASD). Mutations in genes encoding chromatin-remodeling factor Brg1/SmarcA4 and its associated proteins are the genetic causes of several developmental diseases with neurological defects and autistic symptoms. Recent large-scale genomic studies predicted Brg1/SmarcA4 as one of the key nodes of the ASD gene network. We report that Brg1 deletion in early postnatal hippocampal neurons led to reduced dendritic spine density and maturation and impaired synapse activities. In developing mice, neuronal Brg1 deletion caused severe neurological defects. Gene expression analyses indicated that Brg1 regulates a significant number of genes known to be involved in synapse function and implicated in ASD. We found that Brg1 is required for dendritic spine/synapse elimination mediated by the ASD-associated transcription factor myocyte enhancer factor 2 (MEF2) and that Brg1 regulates the activity-induced expression of a specific subset of genes that overlap significantly with the targets of MEF2. Our analyses showed that Brg1 interacts with MEF2 and that MEF2 is required for Brg1 recruitment to target genes in response to neuron activation. Thus, Brg1 plays important roles in both synapse development/maturation and MEF2-mediated synapse remodeling. Our study reveals specific functions of the epigenetic regulator Brg1 in synapse development and provides insights into its role in neurological diseases such as ASD.

Original languageEnglish (US)
Pages (from-to)70-83
Number of pages14
JournalMolecular and Cellular Biology
Volume36
Issue number1
DOIs
StatePublished - 2016

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MEF2 Transcription Factors
Autistic Disorder
Synapses
Chromatin
Genes
Dendritic Spines
Neurons
Chromatin Assembly and Disassembly
Gene Regulatory Networks
Epigenomics
Transcription Factors
Autism Spectrum Disorder
Gene Expression
Mutation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

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title = "Autism-associated chromatin regulator Brg1/SmarcA4 is required for synapse development and myocyte enhancer factor 2-mediated synapse remodeling",
abstract = "Synapse development requires normal neuronal activities and the precise expression of synapse-related genes. Dysregulation of synaptic genes results in neurological diseases such as autism spectrum disorders (ASD). Mutations in genes encoding chromatin-remodeling factor Brg1/SmarcA4 and its associated proteins are the genetic causes of several developmental diseases with neurological defects and autistic symptoms. Recent large-scale genomic studies predicted Brg1/SmarcA4 as one of the key nodes of the ASD gene network. We report that Brg1 deletion in early postnatal hippocampal neurons led to reduced dendritic spine density and maturation and impaired synapse activities. In developing mice, neuronal Brg1 deletion caused severe neurological defects. Gene expression analyses indicated that Brg1 regulates a significant number of genes known to be involved in synapse function and implicated in ASD. We found that Brg1 is required for dendritic spine/synapse elimination mediated by the ASD-associated transcription factor myocyte enhancer factor 2 (MEF2) and that Brg1 regulates the activity-induced expression of a specific subset of genes that overlap significantly with the targets of MEF2. Our analyses showed that Brg1 interacts with MEF2 and that MEF2 is required for Brg1 recruitment to target genes in response to neuron activation. Thus, Brg1 plays important roles in both synapse development/maturation and MEF2-mediated synapse remodeling. Our study reveals specific functions of the epigenetic regulator Brg1 in synapse development and provides insights into its role in neurological diseases such as ASD.",
author = "Zilai Zhang and Mou Cao and Chang, {Chia Wei} and Cindy Wang and Xuanming Shi and Xiaoming Zhan and Birnbaum, {Shari G.} and Ilya Bezprozvanny and Huber, {Kimberly M.} and Wu, {Jiang I.}",
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AU - Zhang, Zilai

AU - Cao, Mou

AU - Chang, Chia Wei

AU - Wang, Cindy

AU - Shi, Xuanming

AU - Zhan, Xiaoming

AU - Birnbaum, Shari G.

AU - Bezprozvanny, Ilya

AU - Huber, Kimberly M.

AU - Wu, Jiang I.

PY - 2016

Y1 - 2016

N2 - Synapse development requires normal neuronal activities and the precise expression of synapse-related genes. Dysregulation of synaptic genes results in neurological diseases such as autism spectrum disorders (ASD). Mutations in genes encoding chromatin-remodeling factor Brg1/SmarcA4 and its associated proteins are the genetic causes of several developmental diseases with neurological defects and autistic symptoms. Recent large-scale genomic studies predicted Brg1/SmarcA4 as one of the key nodes of the ASD gene network. We report that Brg1 deletion in early postnatal hippocampal neurons led to reduced dendritic spine density and maturation and impaired synapse activities. In developing mice, neuronal Brg1 deletion caused severe neurological defects. Gene expression analyses indicated that Brg1 regulates a significant number of genes known to be involved in synapse function and implicated in ASD. We found that Brg1 is required for dendritic spine/synapse elimination mediated by the ASD-associated transcription factor myocyte enhancer factor 2 (MEF2) and that Brg1 regulates the activity-induced expression of a specific subset of genes that overlap significantly with the targets of MEF2. Our analyses showed that Brg1 interacts with MEF2 and that MEF2 is required for Brg1 recruitment to target genes in response to neuron activation. Thus, Brg1 plays important roles in both synapse development/maturation and MEF2-mediated synapse remodeling. Our study reveals specific functions of the epigenetic regulator Brg1 in synapse development and provides insights into its role in neurological diseases such as ASD.

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